Abstract 5154: Targeting the histone demethylase KDM4 subfamily as a potential therapeutic strategy in breast cancer

Abstract

Abstract Epigenetic alterations, including histone modifications, play fundamental roles in breast cancer initiation and progression. We originally identified and cloned the GASC1 (gene amplified in squamous cell carcinoma 1, also known as KDM4C) gene from an amplified region at 9p24 in esophageal cancer cells; and recently demonstrated that KDM4C/GASC1 is amplified and over-expressed in breast cancer, particularly in the aggressive basal subtype. The KDM4C/GASC1 protein belongs to the KDM4 family of histone demethylases, and although KDM4 family members have a high degree of homology, they may play different roles in various types of breast cancer. The goal of this study is to analyze genomic anomalies and expression levels of KDM4 demethylases in breast cancer, and elucidate the fundamental role and mechanism of their dysregulation in promoting breast tumorigenesis. We conducted a large-scale meta-analysis of KDM4 demethylase expression across multiple available gene expression studies in breast cancer. Next, we examined KDM4 expression in a panel of non-tumorigenic and cancerous breast epithelial cell lines using quantitative RT-PCR and Western blot assays. We also assessed global methylation (H3K4, H3K9, H3K27 and H3K36) levels by Western blot in a panel of breast cancer cell lines. Finally, we tested a novel KDM4 inhibitor in breast cancer. We found that the KDM4 members show different expression patterns in subtypes of breast cancer. GASC1/KDM4C expression is high in estrogen receptor (ER)-negative, basal type breast cancers. In contrast, KDM4B expression is significantly higher in ER-positive luminal-type breast cancers. Expression levels of homologs KDM4A and D are not significantly different between ER-+/- breast cancers. Our findings suggest that H3 global methylation levels vary among different breast cancer cell lines. Furthermore, we demonstrated that inhibition of KDM4 with a novel small molecule inhibitor increased H3K9 methylation levels and slowed KDM4-overexpressed breast cancer cell growth in vitro. In summary, our data indicate that the KDM4 histone demethylase family may contribute to the dysregulation of histone methylation status differently in breast cancer subtypes. Moreover, breast cancer cell lines with defined histone methylation levels will provide a useful model for investigating biological and functional roles of KDM4 histone demethylases, and for developing novel anticancer epi-drugs in breast cancer. Citation Format: Andreana Holowatyj, Qin Ye, Lihong Zhang, Jack Wu, Zeng-Quan Yang. Targeting the histone demethylase KDM4 subfamily as a potential therapeutic strategy in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5154. doi:10.1158/1538-7445.AM2014-5154